The human immune system may be broadly subdivided into two separate, interacting subsystems. The central immune system patrols the inner organs and tissues; and the mucosal immune system provides a defensive barrier against microbes that enter the body through the surfaces of the airways, intestines and urogenital tract. While the central immune system has been the subject of intensive study over the last three decades, knowledge of the mucosal immune system, which in humans covers a surface area of approximately 400 m.sup.2 and is therefore by far the larger of the two systems, remains poor.
Intranasal immunization of a variety of vaccine compositions has been reported to favor the development of B cell responses at distal mucosal sites, for example, resulting in vaginal antibody secretion. Among such vaccines are: a recombinant Salmonella typhimurium vaccine expressing a hepatitis virus antigen [Hopkins et al, Infect. Immun., 6:3279-3286 (1995)], a streptococcal surface antigen coupled to the cholera toxin (CT) B subunit [Wu and Russell, Infect. Immun., 61:314-322 (1993)], an HIV peptide given with CT [Staats et al., J. Immunol., 1:462-472 (1996)], a replication competent adenoviral recombinant expressing a herpes virus antigen [Gallichan and Rosenthal, Vaccine, 13:1589-1595 (1995)], and a DNA vaccine with CT as an adjuvant [Kuklin et al., J. Virol., 21:3138-3145 (1997)]. However, the limited understanding of the mucosal immune system has hampered the development of efficacious vaccines to numerous important human pathogens which infect the host via the genital tract mucosal surface. Despite the above reports, vaccines which induce effective mucosal immunity, particularly vaccines to induce protective immunity against sexually transmitted pathogens, which infect humans via the mucosa and which constitute major emerging and re-emerging infectious diseases, are not currently available.
Such agents include human immunodeficiency virus (HIV), human papilloma viruses (HPV), Neisseria gonorrhea, Treponema pallidum, and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). These agents often establish persistent infections once they have avoided the mucosal barrier. Further, systemic immunization capable of protecting against a systemic infection may not protect against a mucosal infection [Lehner et al., Nature Med., 2:767-775 (1996)]. Accordingly, systemic immunization represents a secondary (and possibly ineffective) means of defense once the first line of defense, i.e., mucosal immunity, has been breached.
Vaccine compositions which have been administered systemically or mucosally include adenovirus constructs that express reporter proteins, upon either intravenous inoculation targeting the liver or upon intratracheal application targeting the lung. However, a strong neutralizing antibody response to the adenoviral antigens of the recombinant adenovirus often reduces the rate of infection upon a second application of such recombinant adenovirus as a vaccine construct. These vaccine constructs induce CD8+ T cells reactive to both the reporter transgene protein product and to the viral antigens of the adenoviral construct. This immune response causes clearance of recombinant adenovirus-infected cells from the animal within 10-14 days post-inoculation [Yang et al., 1995, J. Virol., 69:2004-2015; Yang et al., 1995, Gene Therapy, 3:137-144]. Adenoviral recombinants also stimulate CD4+ T helper cells, predominantly of the Th1 type. These T helper cells promote activation of an antibody response which prevents efficacious re-infection upon a second application of the adenoviral vaccine vehicle. Accordingly, the strong immune response to the adenovirus vaccine vehicle curtails the necessary secondary immune response to the antigen product expressed by the recombinant vaccine upon booster immunization.
In order to circumvent this limitation of adenoviral recombinant vectors, genetic vaccines based on plasmid vectors have been tested for their ability to induce a protective immune response in animals. In this regard, prior studies have demonstrated that plasmid-based vaccines, upon systemic application, prime the systemic immune system to a second systemic immunization with a traditional antigen, such as a protein or a recombinant virus [Xiang et al, Springer Semin. Immunopathol., 19:257-268 (1997); J. Schneider et al, Nature Med., 4:397 (1998); M. Sedeguh et al., Proc. Natl. Acad. Sci., USA; 95:7648 (1998)]. However, these plasmid-based vaccines appear to induce only low levels of genital IgA secretion upon co-administration with cholera toxin [Kuklin et al., J. Virol., 71:3138-3145 (1997)]. Therefore, plasmid-based vaccines, while useful for inducing a systemic immune response, may not be adequate for the purposes of generating a protective mucosal immune response.
There is a long-felt and acute need for the design and development of efficacious vaccines to induce or confer mucosal immunity in humans to human pathogens. The present invention satisfies this need.